A number of therapeutic agents have been developed and formulated for use in implantable infusion devices. For example, preservative-free morphine sulfate sterile solution has been formulated for chronic intraspinal (epidural and intrathecal) infusion in the treatment of chronic intractable pain; preservative-free ziconotide sterile solution has been used for chronic intrathecal infusion for the management of severe chronic pain; LIORESAL® Intrathecal (baclofen injection) has been developed for chronic intrathecal infusion for the management of severe spasticity; and floxuridine (FUDR) or methotrexate have been used for chronic intravascular infusion for the treatment of primary or metastatic cancer.
Prior to chronic delivery in an implantable infusion device, a number of studies are performed to determine whether the drug and other components of the formulation are stable in the device (e.g., at 37° C. for 30 days) and compatible with the device (e.g., do not corrode, gum up, or cause fatigue of device components). The formulation may also be adjusted to ensure that the infusion device will properly pump and dispense the fluid (e.g., the viscosity is in a range that will allow long term delivery by the infusion device).
Regardless of the agent to be delivered, obtaining a suitable formulation for chronic delivery via an implantable infusion device can present a number of challenges. The challenges are typically more numerous with large molecules, such as polypeptides, as opposed to small molecules such as the morphine, ziconitide, baclofen, floxuride and methotrexate mentioned above. With large molecules, the tendency to agglomerate and prevent proper flow through an infusion device presents some challenges, as does increased viscosity, which can result in increased wear on the pumping mechanism or the inability to pump.
One class of large molecule therapeutic agents that may be of great interest for use in implantable infusion devices is tumor necrosis factor (TNF) inhibitors, such as TNFalpha inhibitors. In many cases, TNF-alpha inhibitors are antibodies to TNF-alpha, such as inflixamib (REMICADE), adalimumab (HUMERIA), certolizumab (CIMZIA), and golimab (SIMPONI), or circulating receptor fusion proteins, such as enanercept (ENBREL). Steed et al. have described rational design of dominant-negative TNF variants (Science, vol. 301, p. 1895, 2003). Using this approach, Zalevsky et al. reported dominant negative inhibitors of soluble TNF that attenuate experimental arthritis without suppressing innate immunity to infection (J. Immunol, vol. 179, p. 1872, 2007). These agents, which include XPro1595 (XENP1595), may be good candidates for delivery via an implantable infusion device for treatment of TNF-related diseases. However, suitable formulations for use in such implantable devices are lacking.